Sprayable polymers as adhesion barriers

ABSTRACT

A formulation for generating an adhesion barrier that includes a plurality of particles or a dry powder that is made of a polymer combination of at least one biodegradable polymer and at least one water soluble polymer is disclosed. Methods of making and delivering the formulation are further disclosed. The formulation of particles is deposited on a surface of internal body tissue and the deposited formulation absorbs moisture from the tissue and forms a film over the surface. The film acts as an adhesion barrier by reducing or preventing adhesion of the surface to other body tissue.

CROSS REFERENCE TO RELATED APPLICATION

This application claims benefit of and incorporates by reference U.S.Patent Application No. 61/237,669 which was filed on Aug. 27, 2009.

FIELD OF THE INVENTION

This invention relates generally to adhesion barriers and in particularto sprayable and biodegradable polymer adhesion barriers for preventionof post-operative surgical adhesion formation.

DESCRIPTION OF THE RELATED ART

Post-operative surgical adhesions are a normal part of the surgicalhealing processes. Many adhesions are desired, and are an integral andimportant part of the healing of the surgical field. However, adhesionscan also result in unwanted scar tissue between vital structures in thebody and can result in significant post-operative surgical problems ormorbidity. Such adhesions can significantly impact an individual'shealth, well-being and quality of life. The formation of post-operativesurgical adhesions in the abdomen can lead to chronic pain, infertility,and small bowel obstruction (SBO). Adhesions after thoracic and cardiacsurgeries can lead to serious consequences during subsequentre-operative cardiothoracic procedures.

The incidence of adhesions forming after surgical procedures is 100%,with less than 5% of adhesions being caused by inflammation. Adhesionsform after all types of surgeries (abdominal, pelvic, cardiac, thoracic,spinal, plastic, hand, and knee). In the USA, the cost of abdominal andpelvic adhesions to the healthcare system in 1998 was estimated at $1.6billion based on 5.6 million surgical procedures deemed “at risk” fordeveloping postoperative related surgical complications.

Post-operative adhesions are a common, expensive problem for patientsand the healthcare system. Various approaches have been considered toreduce or eliminate post-surgical adhesions. Such approaches includeminimizing trauma to the tissue and tissue exposure to foreign body, andplacing physical barriers between injured tissue. It has been suggestedthat separating the raw to prevent tissue surfaces from coming intocontact with each other during the healing process significantlyminimizes adhesion formation. As the healing process takes weeks tomonths, it will be ideal to keep the surfaces apart, at their naturallocations, without coming into contact with each other during the periodof healing. Physical barriers are helpful in this regard as long as theycan be biocompatible and preferably biodegradable. Additionally, anysuch barrier should be easy to use and fit in with commonly usedsurgical procedures and protocols.

In the case of physical barriers, one of the more traditional methodsinvolves placing a thin polymer-based film at the surgical site, usuallyupon the completion of the surgery. Such a method is presently marketedby Genzyme Biosurgery (Seprafilm®) and Cryolife (CardioWrap®).Limitations of such a method, however, are that the film must be cut tocorrespond to the desired site which adds time to surgery, the membranesare uniform and cumbersome to work with, difficult to configure to theinfinite geometric configurations of the human body, and often difficultto place in hard to reach areas within the surgical field.

Several liquid solutions have also been marketed as adhesion preventionsystems. Adept®, developed by Baxter, for example and Resolve®,developed by Synthemed, are liquids that can be introduced directly tothe intraperitoneal cavity. Specifically, they are used as an instillateafter the surgery, and the entire site is washed with the solution.However, since these products are liquid, they do not remain at thesurgical site for very long past their introduction into and around thesurgical site. As mentioned earlier, it is highly desirable for thematerial to be present and provide the barrier function for apre-determined time period, which could be many weeks.

Gel-based adhesion barriers have been developed to overcome theshortcomings discussed above. SprayGel® by Confluent, for example, is aspray composed of two polymers that combine upon spraying to create afilm on the surgical site. Confluent Surgical markets a similar product,whereby two liquids are combined prior to application to the surgicalsite.

An additional short-coming of the products mentioned above is theirearly absorption within the surgical field. It is desirable to have theadhesion barrier absorb over time, after fibrin and collagen have beenformed to prevent adhesion. This generally takes between 30-60 days andcould be longer in patients with impaired wound healing. The currentgel-based absorbable products are generally absorbed within one week,and thus only prevent adhesions in the early phase of healing. Thus,some adhesion still occurs after the product has been fully absorbed.The adhesion barrier film Cardiowrap is present up to 60 days, but hasthe shortcomings of the film-based barrier discussed above.

Another shortcoming of the mentioned products is the effectiveness ofthe particles in forming a cohesive film that can resist or preventtissue growth or penetration through these barriers. The use ofoverlapping biodegradable particles that are capable of forming aneffective barrier has thus far been ignored.

Ke and Sun describe blends of poly(vinyl alcohol) with poly(L-lactide)which have a higher water absorption than poly(L-lactide) alone.(Starch, Poly(lactic acid) and Poly(vinyl alcohol) Blends, Journal ofPolymers and the Environment, Vol. 11, No.1, (January 2003) They alsoshow that blends of starch/poly(vinyl alcohol)/poly(L-lactide) haveimproved compatibility and mechanical properties over astarch/poly(L-lactide) blend.

Despite advances in the field, additional improvements are desirable. Inparticular, it would be advantageous to provide an adhesion barrier thatis deliverable as an aerosol or by brushing. This will allow direct andexact application to the desired sites, with minimal or no applicationto areas where adhesion is desired. Such a product would have theadvantages of being easier to store than a liquid or gel, while havinggreater contact with the desired treatment site than a liquid. It willbe manufactured to provide prolonged barrier protection. It mayeffectively use particles that are capable of overlapping while formingan effective barrier. It may also contain therapeutic agents to allowfor delivery over time to a specific area of the surgical field. Such anadhesion barrier would be simultaneously easy to use, efficacious andcost effective. At least some of these objectives will be met by theinventions described hereinafter.

SUMMARY OF THE INVENTION

Various embodiments of the present invention include a formulation forgenerating an adhesion barrier comprising: a plurality of particlescomprising a polymer combination, wherein the polymer combinationcomprises at least one biodegradable polymer and at least one watersoluble polymer, wherein when the formulation of particles is depositedon a surface of internal body tissue the deposited formulation absorbsmoisture from the tissue and forms a film over the surface, and whereinthe film is capable of reducing or preventing adhesion of the surface toother body tissue.

Further embodiments of the present invention include a method ofgenerating an adhesion barrier comprising: providing a plurality ofparticles comprising at least one biodegradable polymer; delivering theplurality of particles to a surface of internal body tissue; andallowing the delivered particles to form an adhesion barrier film on thesurface that reduces or preventing adhesion between the surface andother bodily tissue.

Additional embodiments of the present invention include a system forgenerating an adhesion barrier comprising: a pressurized containercomprising an outlet with a valve; and a suspension disposed in thepressured container, wherein the suspension comprises a liquid and aplurality of particles uniformly suspended in the liquid, wherein theparticles comprises a polymer combination including a biodegradablepolymer and a water soluble polymer, wherein the liquid has a boilingpoint such that the liquid evaporates immediately upon exposure toambient or atmospheric conditions, wherein upon opening the valve thesuspension is released through the outlet and the liquid immediatelyevaporates which forms a dispersion of the particles in air.

Other embodiments of the present invention include a method ofmanufacturing an adhesion barrier comprising: forming a first solutionfrom dissolving at least one biodegradable polymer in a first solvent;forming a second solution from dissolving a water soluble polymer in asecond solvent, wherein the first and second solvents are immiscible;blending the first and second solutions to form an emulsion of the firstand second solvent; and forming polymer particles from the blend,wherein each of the polymer particles is a blend of the biodegradablepolymer and the water soluble polymer.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention has other advantages and features which will be morereadily apparent from the following detailed description and theappended claims, when taken in conjunction with the accompanyingdrawings, in which:

FIG. 1A depicts an exemplary particle structure of a formulation that isa blend of a biodegradable polymer and hygroscopic polymer.

FIG. 1B depicts an exemplary particle structure formulation including acore of a polymer or polymer combination and a shell composed of adifferent polymer or polymer combination.

FIG. 2 depicts a schematic spray dry system.

FIG. 3 shows an exemplary set of steps for the manufacture of theinvention.

FIG. 4 shows an exemplary set of steps for the manufacture of theinvention.

FIG. 5A depicts an overhead view of an adhesion barrier film over aselected area of surface region of tissue.

FIG. 5B depicts a cross-sectional view of the film of FIG. 5A.

FIG. 5C depicts an embodiment of an adhesion barrier film with holes orvoid areas.

FIGS. 6A and 6B depicts schematic delivery configurations.

FIG. 7 depicts an exemplary delivery system for delivery of aformulation of particles from a dry powder.

FIG. 8 depicts an exemplary delivery system for delivering a formulationfrom a suspension.

FIGS. 9A and 9B depict the swelling of a PLGA/PVA formulation and aPLGA/PEG formulation.

FIG. 10 depicts a photograph of chronic sheep preparation at the time ofimplant.

FIG. 11 depicts a photograph of a chronic sheep implant at the time ofreexploration, 23 days after the initial implant.

FIG. 12 depicts a photograph of a chronic sheep implant at the time ofreexploration, 23 days after the initial implant.

FIG. 13 depicts a photograph from the same preparation as in FIG. 12showing another view of the PLGA film/barrier over the heart (leftatrial appendage).

FIG. 14 depicts a photograph of a chronic sheep implant at the time ofreexploration, 23 days after the initial implant.

FIG. 15 depicts a photograph from the of chronic sheep implant in FIG.14.

FIG. 16 depicts a photograph of histologic results of the PLGA membrane(film/barrier) depicted in FIG. 15.

DETAILED DESCRIPTION

Although the detailed description contains many specifics, these shouldnot be construed as limiting the scope of the invention but merely asillustrating different examples and aspects of the invention. It shouldbe appreciated that the scope of the invention includes otherembodiments not discussed in detail above. Various other modifications,changes and variations which will be apparent to those skilled in theart may be made in the arrangement, operation and details of the methodand apparatus of the present invention disclosed herein withoutdeparting from the spirit and scope of the invention as described here.

The various embodiments of the present invention disclose a formulationor composition for generating an adhesion barrier, a method of usingsaid adhesion barrier, and methods of manufacturing said adhesionbarrier. Methods of using include, in particular, methods of delivery ofthe formulation to tissue. Additionally, systems for delivery of theformulations are disclosed. The adhesion barrier that is formed from theformulation is a barrier that prevents the abnormal adhesion or union oftissue surfaces due to formation of new fibrous tissue.

The adhesion barrier is bioabsorbable and can be formulated to losestrength or bio-absorb in specific time frames. Upon delivery, theformulation immediately conforms to tissue and forms a film. The filmthat is formed sticks to the tissue and does not require suturefixation.

In general, the formulation can be delivered to form a film thatprovides an adhesion barrier in any part of body on tissue under theskin or within an orifice. Under the skin can include, for example, suchas where there is cutting of tissue or where there in an open surgicalwound. In exemplary embodiments, the formulation can be delivered totissue in various types of surgeries. This tissue can be in regions suchas pelvic, abdominal, thoracic, orthopedic (e.g., hip and knee), neck,or spine surgeries. The formulation can be delivered under the skin totissue endoscopically.

The adhesion barrier is a biodegradable film formed from the formulationthat includes a polymer or combination of polymers. In preferredembodiments, the formulation includes or is in the form of particlesincluding the polymer or combination of polymers. The particles may bedelivered by depositing the particles on living tissue, such as tissueunder or beneath the skin. In certain embodiments, the particles priorto delivery are a dry solid or dry powder containing no or substantiallyno solvent. Substantially no solvent can refer to less than 0.1 wt %,0.01 wt %, or less than 0.001 wt % of solvent in the particles.

The particles are preferably deposited by directing the particles as afinely dispersed form or as an aerosol onto the tissue. An “aerosol”refers to a system or suspension of particles finely dispersed in a gasor liquid. Finely dispersed refers a system of particles in whichagglomeration of the particles in minimized and the particles aredispersed within and are separated by a gaseous medium.

The particles hence form a barrier between the structure to which it isapplied and any other structure on the opposing side of the barrier. Forexample, between the heart and sternum, the heart and lung, the lung andchest wall (perital pleura), the small bowel and abdominal wall(peritoneum), or the liver and colon.

As disclosed in more detail below, the particles can be delivered invarious ways such as by application with a brush, or a toothpaste likeform. In other embodiments described in more detail below, theformulation can be a gel or liquid that includes the polymer orcombination of polymers.

The biodegradable film deposited on the tissue reduces or preventsadhesions from forming between the tissue and other adjacent tissue. Thebiodegradable film has a lifetime appropriate to a particular treatmentapplication. The film maintains sufficient mechanical strength so thatit has mechanical integrity for a period of time. The film then losesmechanical integrity and is eroded or absorbed into the body,disappearing completely from the deposition site over a period of time.

The lifetime of the film can be characterized in terms of the timeperiod that the film maintains sufficient strength to maintainmechanical integrity. Mechanical integrity is the ability of the film tomaintain its shape without cracking or maintain a physical barrier thatprevents contact of the surface of two organs. The lifetime of the filmcan also be characterized in terms of the time for the film to becompletely eroded or absorbed and removed from the deposition site. Thelifetime in terms of strength or to completely absorb can be one to twoweeks, two weeks to a month (or 30 days), one to two months (or 60days), two months to three months (or 90 days), or greater than threemonths. The film last long enough to allow fibrin and collagen to formto prevent adhesion of tissue.

In some embodiments, a pseudo cellular membrane grows on one or bothsides of adhesion barrier film after film formation and becomes abarrier. The body's natural immune response results in the formation ofthe pseudo membrane over the film and becomes a barrier.

In certain embodiments, the formulation includes a plurality ofparticles that include or are composed of a polymer or combination ofpolymers. In some embodiments, the particles include a biodegradablepolymer or a combination of at least two biodegradable polymers. Theterm “polymer” can refer to one type of polymer and can also refer to acombination of polymers. In other embodiments, the particles include acombination of a biodegradable polymer and a water soluble polymer. Inthese and other embodiments, the biodegradable polymer can be non-watersoluble. Preferably, the water soluble polymer is hygroscopic and/orcapable of swelling when it absorbs moisture. The combination caninclude more than one type of biodegradable polymer. The combination canalso include more than one type of water soluble polymer. In the case ofparticles in which individual particles include a biodegradable polymerand a water soluble polymer, the water soluble polymer causes orfacilitates swelling of the particle to swell upon contact with tissue.

In general, the water soluble polymer facilitates formation of the filmby providing adhesion between particles and adhesion of the film to thetissue or biological substrate. The biodegradable polymer providesstructural integrity and strength to the film for a longer period oftime that a water soluble polymer in the absence of a biodegradablepolymer. The lifetime of the film is determined primarily by thedegradation behavior of the biodegradable polymer. Therefore, thebiodegradable polymer has a lifetime in terms of mechanical integrityand erosion that is longer than the water soluble polymer. For example,the biodegradable polymer can have lifetimes in water or bodily fluid ofat least 30 days, 30 to 60 days, or greater than 60 days.

In other embodiments, the particles can include a biodegradable polymeror combination of biodegradable polymers that are hydrolyticallydegradable. In some embodiments, the biodegradable polymers are notwater soluble. Biodegradable polymers include, for example, aliphaticbiodegradable polyesters such as poly(L-lactide-co-glycolide) (PLGA). Inadditional embodiments, the particles can include a polymer that is bothbiodegradable and water soluble, such as PVA. In further embodiments,the particles can be made of a polymer that is a block or randomcopolymer of a biodegradable polymer and a water soluble polymer.

A biodegradable polymer, as used in embodiments of the presentinvention, refers to a polymer that upon exposure to bodily fluidsundergoes chemical degradation that results in chain scission thatresults in reduction in molecular weight of the polymer. One mechanismof chemical degradation is hydrolytic degradation. Chemical degradationcan occur by other means, for example, enzymatic degradation. Thedegradation of a biodegradable polymer can be characterized by (1)reduction in molecular weight due to chemical degradation; (2) reductionand loss of mechanical properties, in particular strength, due toreduction in molecular weight; (3) loss of mechanical integrity due todeterioration of mechanical properties; and (4) erosion or mass lossfrom the degraded polymer arising from dissolution of low molecularweight degradation products in the bodily fluid.

A water soluble polymer, as used in embodiments of the presentinvention, is a polymer that dissolves in water or bodily fluids and isnot necessarily subject to chemical degradation upon exposure tomoisture or bodily fluids. A water soluble polymer can dissolve in wateror bodily fluids, but not be subject to chemical degradation uponexposure to water or bodily fluids, for example, sucrose. A watersoluble polymer can dissolve in water or bodily fluids and also besubject to chemical degradation upon exposure to water or bodily fluids,for example, poly(vinyl alcohol) (PVA) A water soluble polymer may behygroscopic (e.g., polyethylene glycol (PEG)) or may not be hygroscopic(e.g., sucrose). A hygroscopic polymer is a polymer that is capable ofabsorbing or taking up and retaining moisture from a gas containingmoisture, e.g., humid air. A hygroscopic polymer may be capable ofswelling or increasing in size upon absorbing moisture. A swellablepolymer absorbs moisture and swells or increases in volume due to theabsorbed moisture.

After deposition of the particles in moist tissue, the water solublepolymer in the formulation facilitates adhesion or bonding between thedeposited particles. This swelling of the particles causes particles tooverlap which results in the formation of a film or sections of filmthat is free of holes or voids which would expose tissue over which theparticles are deposited. Additionally, the water soluble polymerfacilitates adhesion of the film to the tissue. The water solublepolymers of the formulation also absorbs moisture from the biologicaltissue upon deposition and facilitates adhesion between particles andbetween the particles and the biological tissue.

In certain embodiments, the delivery of the formulation of particlesincludes deposition of small, finely dispersed particles on a selectedsurface region of tissue. The manner of deposition and fine dispersionof particles allow the deposited particles to develop an intimate,conformal contact with the tissue surface. The formulation exhibitswetting and swelling resulting in spreading of the formulation over thetissue surface and formation of an adhesion film or barrier on thetissue surface that has intimae contact with the tissue surface. Theswelled polymer in the film provides strong adhesion or bonding withbiological tissues with the help of the surface tension and forces thatexist at the site of adsorption or contact.

The present invention includes several embodiments of the combination ofthe polymers. In some embodiments, a particle of the plurality ofparticles can include a combination of biodegradable and water solublepolymers. FIGS. 1A-B depict embodiments of polymer combinations inparticles. In FIG. 1A, the formulation includes particles such asparticle 5 that is a blend or mixture 10 of a biodegradable polymer anda water soluble polymer, where the particle can be made partially orentirely of this blend. In some embodiments, the biodegradable polymeris non-water soluble. In these embodiments, the relative composition(e.g., by weight, volume) of the biodegradable and water solublepolymers in the formulation is determined by the composition of thepolymers in the blend. In such embodiments, a particle of the pluralityof particles can be a homogeneous blend or mixture of the biodegradableand water soluble polymers. In some embodiments, the biodegradable andwater soluble polymer are miscible. Miscible refers to the ability ofthe polymer combination to mix homogeneously on a molecular level. Inother embodiments, the biodegradable and water soluble polymers areimmiscible and not capable of forming a molecular homogeneous blend.Immiscible polymer combinations can be mixed or blended, but tend toseparate into separate polymer phases, and thus cannot be mixedhomogeneously on a molecular level. Therefore, in such embodiments, thecombination can be a homogeneous two or more phase dispersion ofbiodegradable and water soluble polymer phases. The number of phasesdepends on the number of polymers that cannot be mixed homogeneously ona molecular level.

In additional embodiments, depicted as FIG. 1B, the formulation includesparticles such as particle 12 that includes a core 14 composed partiallyor entirely of a polymer or polymer combination and a shell 16 composedpartially or entirely of a different polymer or polymer combination. Inone embodiment, the core is composed of a biodegradable polymer(s) andthe shell is composed of a water soluble polymer(s). In anotherembodiment, the core is composed of a water soluble polymer(s) and theshell is composed of biodegradable polymer(s). In these additionalembodiments, the relative composition of the biodegradable and watersoluble polymer in the formulation is the relative weight or volume ofthe respective polymers in the core and the shell. In furtherembodiments, the core can be composed of a blend or mixture of watersoluble and biodegradable polymer, as described above, of abiodegradable polymer and a water soluble polymer and the shell is awater soluble or biodegradable polymer.

In further embodiments, the polymer combination in the formulation is amixture of at least two pluralities of particles, the first and secondpluralities being made of different kinds of polymers or polymercombinations. In a particular embodiment, one plurality of particles iscomposed of a biodegradable polymer and another plurality of particlesis composed of water soluble polymer. The relative composition by weightor volume of the biodegradable and water soluble polymers is therelative weight or volume of the two plurality of particles.

In general, it is desirable for the adhesion barrier or film to berelatively thin. In order to develop a relatively thin film and provideintimate contact with the tissue surface, relatively small particle sizemay be used in the formulation. The mean particle size in theformulation can be 50 nm to 500 microns, or more narrowly, 700 nm to 200microns.

The types of biodegradable and water soluble polymers, the combinationthereof, and the composition thereof influence the quality of the filmthat is formed, the degree of adhesion of the film, and the lifetime ofthe film. In some embodiments, the formulation can be 1-99, 10-90,20-90, 30-90, 40-90, 50-90, 60-90, 70-90, 10-80, 10-70, 10-60, 10-50,10-40, 10-30, 20-80, 30-70, or 40-60 wt % biodegradable polymer orcombinations of such biodegradable polymers. In some embodiments, thecomposition of the formulation can be 10-90, 20-90, 30-90, 40-90, 50-90,60-90, 70-90, 10-80, 10-70, 10-60, 10-50, 10-40, 10-30, 20-80, 30-70, or40-60 wt % water soluble polymer or combination of water solublepolymers.

The biodegradable polymers can include synthetic and naturally occurringhydrolytically degradable polymers. The synthetic hydrolyticallybiodegradable polymer can include hydrolytically degradable polyestersincluding poly(L-lactide-co-glycolide) (PLGA). Exemplary naturallyoccurring biodegradable polymers include chitosan. Exemplarywater-soluble polymers include poly(ethylene glycol) (PEG), PEG blockpolymers, such as di- block or tri-block of PEG/PLGA, PEG/PLA polymerwith PEG segment at the end, PEG random or alternating copolymers, suchas PEG/PLGA copolymer, sucrose, starch, alginate, polyvinylpyrrolidone(PVP), and poly(vinyl) alcohol (PVA). PVA is an exemplary hygroscopicpolymer that is swellable and chemically degradable. With the exceptionof sucrose, all of the above-mentioned water soluble polymers arehygroscopic.

The degradation behavior of the film, in particular, the time for thestrength of the film to degrade resulting in loss of mechanicalintegrity of the film or for complete erosion of the film can be tunedthrough variation of the ratio of lactide to glycolide in the PLGAcopolymer. As the mole percent of L-lactide (LA) decreases from 100% orincreases from 0%, the crystallinity tends to decrease, resulting in adecrease in strength. Additionally, it is known that the in vitrodegradation time of PLGA decreases as the mole percent of LA decreasesfrom 100% or increases from 0%. Therefore, the ratio can be changed toprovide for different degradation rates and amounts of crystallinity fordifferent treatment periods. In general, the PLGA in a formulation canbe between 10% LA/90% GA to 85% LA/15% GA, where the values areexpressed in terms of mole percent. Particular PLGA compositions thatmay be used include 10/90 PLGA, 50/50 PLGA, 70/30 PLGA, 85/15 PLGA, anyof these compositions ±3 mole %, and any commercially availablecompositions identified as having these compositions. A 50/50 PLGAcomposition may provide a film strength lifetime of between one to twoweeks. A 70/30 PLGA composition may provide a film strength lifetime ofbetween 30 and 60 days.

Various combinations of biodegradable polymers with water solublepolymers can be used to obtain desired degradation properties andadhesion. The formulation can include any combination of one or more ofthe disclosed biodegradable polymers and one or more of the disclosedwater soluble polymers. The present invention includes any combinationof the disclosed water soluble polymers.

The formulation can include various combinations of types of polymersincluding:

-   -   biodegradable polymers and water soluble (hygroscopic or        non-hygroscopic) non-chemically degradable polymers;    -   biodegradable polymers and water soluble chemically degradable        polymers;    -   biodegradable polymers, hygroscopic water soluble non-chemically        degradable polymer, and non-hygroscopic water soluble polymer,        and    -   biodegradable polymers, (hygroscopic or non-hygroscopic)        non-chemically degradable water soluble polymers, and chemically        degradable water soluble polymers.

In the above combinations, the water soluble polymers can be hygroscopicor non-hygroscopic.

In some embodiments, the formulation can include any one of thedisclosed compositions of PLGA and one or more of the disclosed watersoluble polymers. In particular, the formulation can include PLGA andany of the combinations of water soluble polymers described in theabove. Exemplary combinations include PLGA with PVA, PEG, starch,alginate, PVP, or any combination thereof. In the formulation, PLGA canvary from 100 wt % to 1 wt % and 99 wt % to 1 wt % of the water solublepolymer or water soluble polymer combination, or more narrowly 10-15 wt%, 15-25 wt %, 25-35 wt %, 35-55 wt %, 55-70 wt %, or 70-90 wt % PLGA.For example, a formulation could include 50 wt % PLGA, 25 wt % PVA and25 wt % starch.

In additional embodiments, the formulation can include any one of thedisclosed compositions of PLGA, another biodegradable polymer, such asChitosan, and one or more water soluble polymers.

Exemplary polymer combinations for the adhesion barrier formulationinclude 70/30 PLGA/PVA; Chitosan/PVA; 70/30 PLGA/Chitosan/PVP;Chitosan/PVP; 70/30 PLGA/PEG; 70/30 PLGA/Starch; 70/30 PLGA/PEGcopolymer/PEG; 70/30 PLGA/PEG copolymer/PLGA/PVA; 70/30 PLGA/PEGcopolymer/PEG/70/30 PLGA; PLGA/Sucrose/PEG; Chitosan/PVA; Chitosan/PVP;PLGA/PVP; and PLGA/Alginate. The weight average molecular weight (Mw) ofthe PLGA copolymer used in the formulations is 600 to 300,000 Daltons,or more preferably, between 6,000 to 200,000 Daltons. Alternatively, theintrinsic viscosity of the PLGA polymers is between 0.2 and 4.0, orpreferably, between 0.8 and 1.2. The Mw of the PEG is between 1000 and100000 Daltons. The Mw of the Chitosan is between 10000 and 300000Daltons. The Mw of the PVP is between 6000 and 300000 Daltons.

The water soluble polymer and biodegradable polymer combination providessynergism in the formation of a suitable adhesion barrier film. Thewater soluble polymer facilitates or provides adhesion between particlesand between the formed film and the tissue. Additionally, the watersoluble polymer also causes swelling of the particles so that theparticles overlap and form a continuous, uniform film free of voids orholes. The biodegradable polymer provides strength and mechanicalintegrity to the film and increases the life time of the film. Asuitable adhesion barrier, i.e., a film that is uniform, free of voidsand has sufficient strength and mechanical integrity for a desired timeperiod is provided by a formulation with an appropriate amount each typeof polymer. These characteristics or features provided by each of thetypes of polymer are balanced to provide a suitable film. For example, afilm that has insufficient strength or has shorter lifetime than desiredcan result from too much water soluble polymer and insufficientbiodegradable polymer.

A measure of the swelling is given by the water uptake of the particles.The water uptake can be between 1-80%, or more narrowly, 20-30 wt %.Water uptake is defined as the maximum amount of water, expressed interms of wt % of water in the particle, absorbed by the particle whenexposed to a moisture. The inventors have found that the water uptake ofparticles between 10-30 wt %, in particular, provides for formation of asuitable film.

As indicated above, in additional embodiments, the particles can be madeof a block polymer or random copolymer including a biodegradable polymerblock and a water soluble polymer block. The physical state of such ablock copolymer depends on factors such as the weight ratio of thebiodegradable and the water soluble polymers and the molecular weight ofthe blocks. In some embodiments, the weight ratio and molecular weightsof the polymers is selected so that particles made from the blockcopolymer is a solid (at room or ambient temperature) and not a liquid,gel, paste, or liquid. Room or ambient temperature is typically between20-30° C. or more narrowly 23-27° C., or at or about 25° C. The blockcopolymers can be diblock, triblock, star block, or, generally, branchedblock copolymers.

In exemplary embodiments, the block copolymer can include PLGA blocksand PEG blocks. A solid block copolymer formulation for particles may bea diblock copolymer with a PLGA: PEG weight ratio of 99:1 to 50:50. Themolecular weight (weight average) of PLGA may be between 6000 and 500000Daltons and PEG between 1000 and 10000 Daltons. A solid block copolymerformulation for particles may be a triblock copolymer with PLGA on twoends with a PLGA: PEG weight ratio of 99:1 to 50:50. The molecularweight (weight average) of PLGA may be between 6000 and 500000 Daltonsand PEG between 1000 and 10000 Daltons. A solid block copolymerformulation for particles may be a triblock copolymer with PEG on twoends with a PLGA: PEG weight ratio of 99:1 to 50:50. The molecularweight (weight average) of PLGA may be between 6000 and 500000 Daltonsand PEG between 1000 and 10000 Daltons.

In some embodiments, the biodegradable polymer can facilitate adhesionof the film to body tissue. For example, Chitosan is known to haverelatively strong adhesion to internal biological tissue. In additionalembodiments, the water soluble polymer may have a relative weakinteraction, and thus, poor adhesion with the biological tissue. Forexample, alginate has end groups that are expected to have a relativelyweak interactions with biological tissue. Thus, a formulation with thecombination of Chitosan and alginate may have strong adhesion tobiological tissue.

Examples of biodegradable polymers that may be suitable for use with theformulations and methods described here include, but are not limited to,aliginate, cellulose and ester, dextran, elastin, fibrin, hyaluronicacid, polyacetals, polyarylates (L-tyrosine-derived or free acid),poly(a-hydroxy-esters), poly(B-hydroxy-esters), polyamides, poly(aminoacid), polyalkanotes, polyalkylene alkylates, polyalkylene oxylates,polyalkylene succinates, polyanhydrides, polyanhydride esters,polyaspartimic acid, polybutylene diglycolate, poly(caprolactone),poly(caprolactone)/poly(ethylene glycol) copolymers, poly(carbonate),L-tyrosine-derived polycarbonates, polycyanoacrylates,polydihidropyrans, poly(dioxanone), poly-p-dioxanone,poly(epsilon-caprolactone),poly(epsilon-caprolactone-dimethyltrimethylene carbonate),poly(esteramide), poly(esters), aliphatic polyesters, poly(etherester),poly(ethylene glycol)/poly(orthoester) copolymers, poly(glutarunicacid), poly(glycolic acid), poly(glycolide),poly(glycolide)/poly(ethylene glycol) copolymers,poly(glycolide-trimethylene carbonate), poly(hydroxyalkanoates),poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), poly(iminocarbonates), polyketals, poly(L-lactic acid), poly(L-lacticacid-co-glycolic acid), poly(L-lactic acid-co-glycolicacid)/poly(ethylene glycol) copolymers, poly(L-lactide),poly(L-lactide-co-caprolactone), poly(DL-lactide-co-glycolide),poly(L-lactide-co-glycolide)/poly(ethylene glycol) copolymers,poly(L-lactide)/poly(ethylene glycol) copolymers,poly(L-lactide)/poly(glycolide) copolymers, polyorthoesters,poly(oxyethylene)/poly(oxypropylene) copolymers, polypeptides,poly(DL-lactic acid), poly(DL-lactic acid-co-glycolic acid),poly(DL-lactic acid-co-glycolic acid)/poly(ethylene glycol) copolymers,poly(DL-lactide), poly(DL-lactide-co-caprolactone),poly(DL-lactide-co-glycolide)/poly(ethylene glycol) copolymers,poly(DL-lactide)/poly(ethylene glycol) copolymers,poly(DL-lactide)/poly(glycolide) copolymers, polyphosphazenes,polyphosphoesters, polyphosphoester urethanes, polypropylenefumarate-co-ethylene glycol), poly(trimethylene carbonate), polytyrosinecarbonate, polyurethane, PorLastin or silk-ealastin polymers, spidersilk, tephaflex, terpolymer(copolymers of glycolide, lactide ordimethyltrimethylene carbonate), and combinations, mixtures orcopolymers thereof.

Additional polymers include poly(N-acetylglucosamine) (Chitin),poly(3-hydroxyvalerate), poly(3-hydroxybutyrate),poly(4-hydroxybutyrate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate),poly(L-lactide-co-caprolactone), poly(DL-lactide-co-caprolactone),poly(glycolide-co-caprolactone), poly(trimethylene carbonate), polyesteramide, poly(glycolic acid-co-trimethylene carbonate),co-poly(ether-esters) (e.g. PEO/PLA), polyphosphazenes, PVA, PVP,starch, biomolecules (such as fibrin, fibrinogen, cellulose, collagenand hyaluronic acid), polyurethanes, rayon, rayon-triacetate, cellulose,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,and carboxymethyl cellulose.

Several embodiments of making particles of the formulation includedissolving a polymer or polymers in a solvent for the polymer to form apolymer solution. In some embodiments, the particles can be formed fromthe solution using a spray-dry process.

A solvent for a polymer is a liquid that is capable of dissolving thepolymer to form a solution containing the polymer mixed with the liquidon a molecular level with at least a 0.1 wt % concentration of polymer.Some common solvents for PLGA include tetrahydrofuran (THF), acetone,and ethyl acetate. Some solvents for 50/50 PLGA include acetone,methylene chloride, ethyl acetate, chloroform, dimethylformamide (DMF),THF, hexafluoroisopropanol (HFIP), etc. Some solvents for 70/30 PLGAinclude acetone, methylene chloride, ethyl acetate, chloroform, DMF,THF, HFIP, etc. Solvents for Chitosan include acetic acid or water/acidsolvent system.

Spray drying is a method of producing a plurality of particles or drypowder with little or no residual liquid or solvent from a liquid (e.g.,a solution) or slurry by rapidly drying the liquid or slurry with a hotgas. A relatively consistent or narrow particle size distribution can beobtained with spray drying. Typically heated air is the heated dryingmedia; however, other gases such as nitrogen, oxygen, carbon dioxide, orargon may be used.

A spray dryer apparatus includes an atomizer or spray nozzle to dispersethe liquid or slurry into a controlled drop size spray. Exemplarynozzles include rotary nozzles, single-fluid pressure swirl nozzles, ora two-fluid or ultrasonic nozzles. Drop sizes can be in a range from 50nm to 500 microns, or more narrowly, from 700 nm to 200 microns diameterrange.

FIG. 2 depicts a schematic spray dry system 20. Spray dry system 20includes a drying chamber 22, nozzle 24, heater 26, and a particlecollector 28. A drying gas enters, as shown by an arrow 30, system 20via heater 26. A solution containing dissolved polymer is fed intonozzle 24, as shown by an arrow 32, and atomizes the solution and spraysfine droplets 34 with a narrow size distribution into drying chamber 22.The solvent in the droplets evaporates as the droplets fall and becomesolid particles 36 which are collected in collector 28. The solidparticles can be separated using an electrostatic particle collector,filtration, centrifugation, or a combination thereof. The inlettemperature of the heating gas may be controlled by a temperaturesensor.

An exemplary spray dryer that may be used to obtain particle sizes inthe range 50 nm to 300 microns, for example, for a formulation of thepresent invention of Chitosan/PVP. Process parameters of the spray dryprocess include the temperature of the heating gas, droplet size,velocity of droplets, solution concentration, feeding rate, atomizer oratomization pressure, inlet temperature, outlet temperature, etc. Theatomization pressure can be 0.01 to 1 MPa, or more narrowly0.1 and 0.5MPa. The inlet temperature can be 50 to 300° C., or more narrowlyl00 and200° C. The outlet temperature can be −20 to _80° C., or more narrowlybetween 0 and 50° C. . The spray rate can be 0.1 to 5000 ml/min. Theconditions will depend on the size of spray dryer, operation temperatureand particles size requirement, etc.

A formulation containing a mixture of biodegradable polymer particlesand water soluble polymer particles can be made by forming the differenttypes of particles in separate processing steps and physically blendingthe particles together. An exemplary process for manufacturing theparticles for such a formulation is shown in FIG. 3. In Step 1, abiodegradable polymer or polymers is dissolved into an organic orinorganic solvent. A biodegradable polymer or combination ofbiodegradable polymers may be that provides the film forming propertiesand desired treatment period of the end product. The resulting solutionof biodegradable polymer and solvent can vary in concentration between0.01 to 25 wt %, or more narrowly, between 0.2 to 10 wt % ofbiodegradable polymer. In particular, a solution of 70/30 PLGA inacetone or other solvents may be between 0.2 and 10 wt % 70/30 PLGA. InStep 2, the resulting solution is then sprayed and dried to produceparticles of the biodegradable polymer.

Particles of water soluble polymer are made in a similar manner. A watersoluble polymer is dissolved in water with a concentration of between0.01 and 25 wt % polymer, or more narrowly, between 0.1 and 10%.Exemplary concentrations of PEG, sucrose, starch can be 1-3 wt %, forexample, 2%. A concentration of PVA in a solution is between 0.1 and 10wt %. A suitable solvent for PVP includes water and a concentration ofPVP in a solution is between 0.1 and 10 wt %.

In Step 3, the particles of biodegradable polymer are blended withparticles of water soluble polymer to produce a biodegradable and watersoluble particle mixture.

A formulation of particles that are a blend or mixture of biodegradablepolymer and water soluble polymer can be formed by spray drying anemulsion containing the two types of polymers. An exemplary process formanufacturing such particles of such formulations is shown in FIG. 4. Asshown in Step 1, two separate polymer solutions are prepared, onesolution being a biodegradable polymer dissolved in a first solvent andthe other solution being a water soluble polymer dissolved in a secondsolvent. The first solvent is typically an organic solvent and thesecond solvent is typically water or an aqueous solution. The propertiesof the first and second solvent are such that a two phase liquid mixtureis formed. Immiscibility of the first solvent and the second solventallow the formation of a two phase liquid mixture. The ratio of theamount of biodegradable polymer dissolved in the first solvent and theamount of water soluble polymer dissolved in the second solventcorresponds to the desired ratio of the two polymers in the particles.

For example, PLGA can be dissolved in acetone or chloroform and PEG orPVP can be dissolved in water. Chitosan can be dissolved in an aqueoussolution that is acidic, since its solubility is increased in an acidicenvironment. For instance, an aqueous solution can have between 0.05 and5 wt % acetic acid.

As shown in Step 2, the two solutions are mixed to form an emulsioncontaining two liquid phases. The solution having the smaller volumewill be dispersed within the solution with the larger volume. Therelative volume of the two solutions depends on the concentrations ofpolymer in each and the desired relative composition of polymers in theparticles. For given solution concentrations, the relative volume isadjusted so that the relative amount of the polymer in each solution isthe desired relative amount in particles made from the solutions.Specifically, the ratio the volume of solution 1 (V1) to the volume ofsolution 2 (V2) is:

V1/V2=(p1/p2)×(C2/C1)

wherein p1 and p2 are the weight percent of polymer 1 and polymer 2,respectively, of the polymer blend of resulting particles and C2 and C1are the concentrations of the solution of polymer 1 and polymer 2,respectively.

For example, 70/30 PLGA and PVA particles (70 wt % PLGA and 30 wt % PVA)can be formed from a 1 wt % PVA solution and a 1-5 wt % solution ofPLGA. To obtain 70/30 particles using the 1 wt % PLGA solution, theratio of the volume of the PLGA solution to the volume of the PVAsolution is (70/30)×(1/1) or about 2.33. In this case, the PVA solutionwill be dispersed in the PLGA solution. Similarly, to obtain 70/30particles using 5 wt % PLGA solution, the ratio of the volume of thePLGA solution to the volume of the PVA solution is (70/30)×(1/5) whichis about 0.47. In this case, the PLGA solution will be dispersed in thePVA solution.

In some embodiments, the aqueous phase is dispersed in the organic phaseor alternatively, the organic phase is dispersed in the aqueous phase.In some embodiments, the two solutions are combined slowly and thesolutions may be stirred on sonicated with a sonic mixer to facilitateformation of a stable emulsion.

In step 3, a spray dryer is used to form particles from the emulsion.The particles formed will be a blend of the biodegradable polymer andthe water soluble polymer, e.g., a blend of PLGA and PVA. The spraydrying process is described in detail below.

In some embodiments, a biodegradable polymer and a water soluble polymercan be dissolved in the same solvent. In an exemplary embodiment,Chitosan and a water soluble polymer can be dissolved in an aqueousacidic solution of acetic acid. Particles of Chitosan and the watersoluble polymer can be formed from the solution by spray drying.

In additional embodiments, the solution or emulsion containing thebiodegradable and water soluble polymer can be concentrated prior tospray drying. In such embodiments, at least some of the organic solventcan be removed, for example, through evaporation. This can beadvantageous because this reduces the time required by the spray dryingprocess to form the particles. In spray drying, the time to formparticles from a volume of solution or emulsion increases with thevolume of solution. In these embodiments, a portion of the organicsolvent is evaporated from the emulsion or solution. In someembodiments, a portion of the organic solvent may be removed or all ofthe organic solvent may be removed. In exemplary embodiments, less than10 vol %, 10-20 vol %, 20-30 vol %, 30-60 vol %, 60-80 vol %, or 80-100vol % of the organic solvent can be removed. The evaporation can timecan be, for example, performed over a period of 1-8 hours. Theevaporation can be performed at room temperature or, alternatively, theemulsion can be heated to a temperature below the boiling point of theorganic solvent.

In these embodiment, removal of the organic solvent can result in theformation of a solution, elution, or system having a uniform milkyappearance. The milky appearance is due to the presence of fineparticles that are a blend of the polymers in the emulsion that arelikely in the range of 300 nm to 20 microns. Although particles haveformed from previously dissolved polymers, some of the polymers may alsoremain dissolved in the respective solvents in the emulsion. The milkysolution may then be spray dried to form the blended particles frompolymer that remains dissolved after mixing the organic and aqueoussolutions.

The milky system may be characterized as a colloid or colloidal systemor a suspension. A colloid is a type of chemical mixture where onesubstance is dispersed evenly throughout another. The particles of thedispersed substance are only suspended in the mixture, unlike asolution, where they are completely dissolved within. This occursbecause the particles in a colloid are larger than in a solution—smallenough to be dispersed evenly and maintain a homogenous appearance, butlarge enough to scatter light and not dissolve. Because of thisdispersal, some colloids have the appearance of solutions. A colloidalsystem includes at least two separate phases: a dispersed phase (orinternal phase) and a continuous phase (or dispersion medium). Acolloidal system may be solid, liquid, or gaseous. The particles of acolloidal system have dimensions between 2 to 1000 nm. In the case of athe milky suspension, the polymer particles are the dispersed phase andthe solvent(s) are the dispersion medium.

Suspensions are homogeneous mixtures with particles in a continuousphase that have diameters greater than 1000 nm. The size of theparticles is great enough so they are visible to the naked eye. Bloodand aerosol sprays are examples of suspensions. Suspensions are “murky”or “opaque”. They do not transmit light. Suspensions separate onstanding.

In other embodiments, removal of the organic solvent can result in theformation of a nonuniform suspension of particles in the solution. Theparticles of the nonuniform suspension are larger and the particle sizeis likely in the range of 1 to 150 microns. Dissolved polymer is alsostill present in the solution. The suspension may then be spray dried toform the blended particles from polymer that remains dissolved.

Whether or not a milky system is formed depends on several factorsincluding the miscibility of polymers, ratio of polymer matrix, solutionconcentration, mixing speed and vaporization control of solvent, etc.

The particles formed by spray drying the emulsion with the milkyappearance result in a formulation with smaller particles than spraydrying the suspension. The formulation formed from the former hasparticles in the range 0.3 to 20 microns and the latter in the range 1to 150 microns.

Additionally, a particle blend can have more than one biodegradablepolymer, more than one water soluble polymer, or a combination thereof.The procedure described above can be generalized to such blends. In anexemplary embodiment, a blend including two water soluble polymers canbe obtained by forming a solution containing the two polymers which ismixed with a solution of biodegradable polymer. For example, theparticle can contain PVA and PVP or PEG and sucrose. Alternatively,separate solutions of the water soluble polymer can be mixed with thebiodegradable polymer solutions. As indicated above, particles can be ablend of more than one biodegradable polymer with a water solublepolymer, for example, PLGA, Chitosan, and a water soluble polymer.

Additionally, a blend including two biodegradable polymers can beobtained by forming a solution containing the two polymers which ismixed with a solution of water soluble polymers. Particles containing ablend of PLGA, Chitosan, and a water soluble polymer can be obtained bymixing a solution of Chitosan with separate solutions of PLGA and thewater soluble polymer. Alternatively, an aqueous acidic solution ofChitosan and a water soluble polymer can be mixed with a PLGA solution.

In other embodiments, a solution of two or more biodegradable polymerscan be formed by dissolving the polymers in the same solvent. An exampleis PLGA and PLGA-PEG block polymer which can dissolve in acetone toproduce swellable polymer particles. Another example is PLGA polymerwhich can dissolve into liquid PEG (low molecular weight PEG), forexample, PEG with a molecular weight of 400 g/mole (weight or numberaverage).

As discussed above, particles can include or be composed entirely of ablock copolymer of a biodegradable polymer and a water soluble polymer.The block copolymer particles can be made from a solution formed bydissolving the block copolymer in a solvent. In one embodiments, thesolution can be spray dried to form the particles. In anotherembodiment, the solvent may be evaporated to allow formation of asuspension of particles in the solution or colloid or an elution. Theresulting suspension or colloid or elution can then be spray dried toform the particles. The solvent can be an organic solvent, such asacetone or chloroform. Alternatively, the solvent can be water.

The solvent selection can be based on the solubility of the blockcopolymer. In one embodiment, a solvent is selected to allow formationof at least a 0.1 wt % of block copolymer solution, between 0.1-1 wt %,or at least 1 wt % block copolymer solution. The solubility of the blockcopolymer in an organic solvent or water depends on the relativecomposition of the biodegradable polymer, such as PLGA, and the watersoluble polymer, such as PEG. The larger the mole percent of PLGA, themore likely the block copolymer will be soluble or more soluble in anorganic solvent. Alternatively, the larger the mole percent of the watersoluble polymer, the more likely the block copolymer will be soluble ormore soluble in water.

The particle size from spray drying can be influenced or controlled inseveral ways. The particle size depends process parameters, such asatomization pressure. As shown below in Example 6A, an increase inatomization pressure can increase the particle size. The concentrationof the polymer and the relative concentration of the component polymersin the formulation solution can also influence the particle size.Additionally, a surfactant in the formulation solution can influenceparticle size. The surfactant can be added to the formulation solutionprior to spray drying. As indicated in Example 6C, addition of mannitolto PLGA/Chitosan/PVP formulation solution increases the particle size.

In some embodiments, the resulting biodegradable and water solubleparticles formed from the methods described herein may be larger thandesired for formation of a suitable adhesion barrier film. The particlesmay be reduced in size through one method, or any combination ofmethods. For example, the particles are reduced mechanically by grindingin a fine grinding mill. Additionally or alternatively, the particlesare reduced chemically by exposure to a solvent that dissolves at leasta portion of a polymer in the particles. The exposed particles may thenbe dried, filtered, or a combination thereof. Alternatively, if a largerparticle size is desired, the particles may be compounded to a largersize using methods that include, but are not limited to, compacting,coating, and pelleting.

Further embodiments of the present invention include delivery of theformulation of particles to internal body tissue. The embodimentsinclude depositing the particles on the internal body tissue to allowformation of a thin film over a selected area of the tissue. Upondeposition on the tissue, the particles absorb moisture from the tissue,swell and overlap which result in the formation of a film over theselected area. A sufficient amount of formulation is deposited to form acontinuous film over the selected tissue area

The film is preferably delivered so that it is relatively uniform inthickness and surface texture over the selected area of tissue.Additionally, the film is preferably free or substantially free of holesor void areas that expose tissue in the selected region. Such exposedareas may be susceptible to the formation of adhesions since they allowtissue to tissue contact. Furthermore, the film is preferably thickenough so that the film maintains mechanical integrity and coverage ofthe selected area for a desired time frame. A relative uniformity inthickness reduces or prevents the premature exposure of portions oftissue prior to a desired time frame. The thickness of the film ispreferably between 300 nm and 800 um, or more narrowly, between 1 um and200 um. The film should not be so thick that it causes adverse effectssuch as clumping, and an extreme foreign body reaction, which may inturn result in the development of a thick pseudo-membrane, and hence, becounter-productive to the desired end result. Extreme thickness may alsoalter the absorption time.

FIG. 5A depicts an overhead view of a surface region 60 of the surfaceof tissue that includes an adhesion barrier film 62, as describedherein, over a selected area of surface region 60. Film 62 is free ofany holes or voids and has a relatively uniform thickness. FIG. 5Bdepicts a cross-sectional view of film 62 showing the thickness, Tf, offilm 62 and an interface 64 between film 62 and tissue 60. FIG. 5Cdepicts another embodiment of a film 66 over tissue region 60 that hasholes or void areas 68 that could be due to unsatisfactory delivery ofthe formulation.

In certain embodiments, the particles are deposited or directed onto thesurface of tissue as a finely dispersed suspension or as an aerosol toprovide the desirable characteristics described above. The particles maybe deposited in a dry form suspended in a gas. Delivery in a manner thatreduces or minimizes agglomeration of the particles facilitatesformation of a thin film with relative uniform thickness. Additionally,the delivery should be performed in a manner that allows a closeintimate contact of particles with the tissue so that a film forms withconformal coverage that has close, intimate contact with the surface.The intimate, conformal contact facilitates strong adhesion of the filmto the tissue since it is believed that the particles swell into tissuewhich allows intermingling of particle molecules and tissue moleculesthat enhances adhesion. Delivery in the form of particles, followed byswelling and film formation is expected to provide a more intimate,conformal contact with tissue than, for example, a preformed film orsheet applied to the tissue surface.

The synergistic effect of the formulation characteristics and the mannerof delivery provide for a film with the desired characteristics.Formulation characteristics include a polymer combination that providesfor adhesion of particles to each other and adhesion to tissue, swellingof particles to form a film, and degradation behavior of film thatremains for desired time frame.

FIGS. 6A and 6B depict schematic delivery configurations. The particles100 are stored in an aerosol delivery device 200. Aerosol deliverydevice 200 is any pressurized or unpressurized compailment including amechanism of propelling the particles from within the delivery device200 to a selected area of tissue. The delivery device 200 may contain anactuator 230, which, when depressed, as shown by an arrow 235, releasespressure from within the delivery device 200 to propel the particlesfrom within the delivery device to the desired site. Once the particlescontact the internal tissue at a surgical site, they will swell to forman adhesion barrier film 110. Optionally, as shown in FIG. 6B, a tube237 may be connected to actuator 230, to allow greater control andaccuracy in the delivery of the particles to the desired site. Thedistal end 232 can be manipulated to direct particles are specific areasof the tissue.

In some embodiments, the formulation of particles may be delivered froma container in which the particles are stored as a dry powder. Theparticles may be drawn out of an outlet of the container by a pressuredifferential between the interior of the container and the outlet, thepressure differential being a lower pressure at the outlet than theinterior of the container. The drawn out particles may be directed inthe form of a fine dispersion in a gas onto a region of tissue.

In one embodiment, the pressure differential can be created bypressurizing the interior of the container above atmospheric pressure. Avalve at the outlet can allow for a controlled release of particles. Theparticles that are drawn out through the valve can be dispersed througha hose, nozzle, atomizer, or some other means for deposition on thetissue.

In another embodiment, the pressure differential can be created by astream of gas flowing past the outlet of the container. The particlesmay be drawn out of the outlet and in the stream of gas in a dispersedform. The dispersed stream of particles may be directed at a selectedregion of tissue and deposited thereon. In a further embodiment, inaddition to the stream of gas, the container may be pressurized aboveatmospheric pressure to increase the velocity of the stream of gas,which facilitates intimate contact of the particles with tissue whendeposited.

FIG. 7 depicts an exemplary delivery system 80 for a formulation ofparticles. System 80 includes a container 82 which includes particles 84in a dry power form. A tube 86 is disposed within container 82 with aninlet 88 and an outlet 90. Container 82 and tube 86 are sealed when notdelivering particles. Tube 86 has a valve 92 that allows fluidcommunication between the interior and exterior of container 82. A tube94 is positioned to be in fluid communication with tube 86 when valve 92is open. A stream of gas, as shown by arrow 96, is passed through tube94. The stream of gas, for example, may come from an oxygen or airsupply in an operating room. When valve 92 is opened, particles aredrawn out of container 82, as shown by an arrow 88, through tube 86 andinto tube 94 by a pressure differential between tube 86 and 94 createdby the flow of the stream of gas in tube 94. The particles that aredrawn out are dispersed in the stream of gas 96. The dispersedparticles, as shown by an arrow 98, pass through tube 94 and then aredeposited onto a tissue surface.

In other embodiments, the formulation of particles may be delivered froma pressurized container that includes a suspension of the particles in aliquid propellant. In such embodiments, the particles may be uniformlydispersed within the suspension. The liquid may be selected so that theparticles are uniformly dispersed and agglomeration of particles isreduced or minimized. The container may have a valve that allows fluidcommunication between the interior and exterior of the container so thatwhen the valve is released the suspension is released from thecontainer.

In some embodiments, the propellant is selected so that it is a liquidat room or ambient temperature and the pressure in the container andwhich immediately evaporates or flashes when it exits the container atatmospheric pressure and room temperature. Therefore, the particles aredelivered as a dispersed spray or stream onto the tissue without theliquid propellant. Exemplary liquid propellants includehydrofluoroalkanes (HFA) such as HFA 134 and HFA 227ea.

FIG. 8 depicts an exemplary delivery system 100 for delivering aformulation of particles from a suspension. System 100 includes acontainer 102 which includes a suspension 104 of particles in a liquidpropellant. The container is pressurized to a pressure above atmosphericpressure. A tube 106 is disposed within container 102 with an inlet 108and an outlet 110. Container 102 and tube 106 are sealed when notdelivering particles. Tube 106 has a valve 112 which allows fluidcommunication between the interior and exterior of container 102. Whenvalve 112 is opened, suspension 104 is drawn out of container 102, asshown by an arrow 113, through tube 106. The liquid in the suspensionevaporates immediately or flashes and a dispersed stream or spray ofparticles, as shown by arrow 114, that can be deposited onto a tissuesurface.

The present invention includes additional formulations of a combinationof biodegradable and water soluble polymers. In one embodiment, theparticles can be mixed with a liquid to form a slurry. Exemplary liquidsinclude water, acetone, and alcohol.

In alternative embodiments, the formulation used for forming theadhesion barrier can be a liquid, gel, or paste that includes abiodegradable polymer and a water soluble polymer. In some embodiments,the formulation can be a liquid at a lower temperature and forms ahigher viscosity liquid, gel, or paste at higher temperatures. Inparticular, the formulation can be liquid at room or storage temperatureand be a higher viscosity liquid, gel, or a paste at body temperature

A liquid formulation can be delivered to tissue by, for example,brushing or spraying the formulation on to the surface of the tissue. Aformulation having a transition to a more viscous liquid, gel, or pasteat a temperature between room and body temperature will then exhibitsuch a transition after being applied to the tissue.

A liquid, gel, or paste formulation can be made by dissolving abiodegradable, polymer within a water soluble polymer. The water solublepolymer can be a liquid, gel, or paste. The physical state of the watersoluble polymer (liquid, gel, or paste) depends on the molecular weightof the water soluble polymer. A liquid has a lower molecular weight thana gel or paste. An exemplary formulation is PLGA and PEG. A liquidformulation at room temperature can be formed using PEG with a Mwbetween 300-400 g/mole. PLGA can be mixed or dissolved in the PEG toform a liquid. The liquid formulation can be 1-50 wt % PLGA and 99-50 wt% of PEG. Such a liquid exhibits a transition from a liquid to a gel orpaste between room and body temperature and is a gel or paste at bodytemperature. A gel at room temperature can be formed by mixing PLGA withPEG gel. The Mw of the PEG is between 100 and 1000.

Additional methods may be applied to deliver a formulation to bodytissue. In one embodiment, a formulation can be disposed in a squeezablecontainer such as a tube. The formulation can be delivered by squeezingthe tube in a manner similar to an ointment. In such embodiments, theformulation may be dry particles, a gel or paste system, or a highlyviscous slurry. In other embodiments, a formulation of dry particles,gel or paste, or slurry can be sprayed or brushed onto tissue.

In additionally embodiments, a formulation of particles can be disposedin a container having a delivery end that has a plurality of smallholes. The particles are delivered by shaking the container over aselected region of tissue.

Additionally, during any part of the process of making the formulation,other compounds may be added to ameliorate the usability or to providetherapeutic value of the adhesion barrier. For example, a biocompatibledye is added to promote visibility of the adhesion barrier.

Additionally or alternatively, therapeutic agents such as drugs areadded, for example by mixing or introducing said drug into the polymermatrix during any of the steps of manufacture.

Exemplary therapeutic agents include hemostatic or antihemorrhagicagents to reduce or inhibit bleeding in a selected region of tissue.Hemostatic agents can include those classified as systemic, local,organic, and chemical. Systemic drugs work by inhibiting fibrinolysis orpromoting coagulation and include antifibrinolytics, vitamin K,fibrinogen, and blood coagulation factors. Locally-acting hemostaticagents work by causing vasoconstriction or promoting plateletaggregation. Organic agents include thrombin coagulation factor,microfibrillar collagen, and polysaccharides, such as starch. Chemicalhemostatic agents include Chitosan, hemCon, zeolites, and styptics.Styptics work by contracting tissue to seal injured blood vessels.

Another type of drug can include chemotherapeutic agents which includes,but are not limited to, paclitaxel, protin-bound paclitaxel, alkylatingagents, antimetabolites, anthracyclines, plant alkaloids, topoisomeraseinhibitors, and other antitumour agents, plant alkaloids and terpenoids,vinca alkaloids, podophyllotoxin, topoisomerase inhibitors, antitumourantibiotics etc.

An exemplary drug to be introduced in the formulation includes ananti-adhesion agent or an anti-fibrin growth agent. As another example,an anti-inflammatory drug can be added. The anti-inflammatory drug canbe a steroidal anti-inflammatory agent, a nonsteroidal anti inflammatoryagent, or a combination thereof. In some embodiments, anti-inflammatorydrugs include, but are not limited to, alclofenac, alclometasonedipropionate, algestone acetonide, alpha amylase, amcinafal, amcinafide,amfenac sodium, amiprilose hydrochloride, anakinra, anirolac,anitrazafen, apazone, balsalazide disodium, bendazac, benoxaprofen,benzydamine hydrochloride, bromelains, broperamole, budesonide,carprofen, cicloprofen, cintazone, cliprofen, Clobetasol propionate,clobetasone butyrate, clopirac, cloticasone propionate, cormethasoneacetate, cortodoxone, deflazacort, desonide, desoximetasone,dexamethasone dipropionate, diclofenac potassium, diclofenac sodium,diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate,diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab,enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole,fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac,flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate,flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate,fluquazone, flurbiprofen, fluretofen, fluticasone propionate,furaprofen, furobufen, halcinonide, halobetasol propionate, halopredoneacetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol,ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole,intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen,lofemizole hydrochloride, lomoxicam, loteprednol etabonate,meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate,mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate,momiflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone,olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone,paranyline hydrochloride, pentosan polysulfate sodium, phenbutazonesodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicamolamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone,proxazole, proxazole citrate, rimexolone, romazarit, salcolex,salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin,sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate,tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide,tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium,triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin(acetylsalicylic acid), salicylic acid, corticosteroids,glucocorticoids, tacrolimus, pimecorlimus, prodrugs thereof, co-drugsthereof, and combinations thereof.

Additionally, the resulting adhesion barrier composition may be used inconjunction with other types of adhesion barriers such as film adhesionbarriers. In this situation, the particles and the film may have varyingdegrees of biodegradability, or may contain various drugs or drugquantities.

EXAMPLES Example 1 Particle Size Analysis

The particle sizes of two formulations of particles were measured. Theparticles were formed by spray drying. Each of the formulations areparticles that are a blend of 70/30 PLGA and a water soluble polymer. Apinch of a powder formulation was added to about 3 mL of water in a testtube and mixed well to form uniform dispersion to measure particle sizedistribution. The dispersed liquid was transferred to a curette and theparticles size was determined using Malverns Zeta Sizer obtained MalvernInstruments Ltd, Worcestershire, UK.

TABLE 1 Particle size of formulations. Formulation Mean particlediameter (nm) PLGA/PEG (80:20 mole %) 723.9 PLGA/PVA (80:20 mole %)1404.2

Example 2 Water Absorption

The water absorption was measured for four formulations of particlesthat are blends of 70/30 PLGA and a water soluble polymer. A solution ofbiodegradable and water soluble polymer combination was spread over asurface and allowed to air dry to form a film. The polymer films werecarefully removed and allowed dry in an oven at 60° C. for about 12hours.

The initial weight of the dried films were recorded and immersed intowater. The films were removed, blotted with tissue paper to remove anyexcess water from film, and weighed. The weight gain of the films wascalculated and is shown in Table 2.

TABLE 2 Water absorption of formulations. Formulation % wt gain PLGA PEG(70:30) 88.78 PLGA/PVA (70:30) 67.44 PLGA/PEG (80:20) 16.00 PLGA/PVA(80:20) 24.36

Example 3 Swelling Properties

The formulation powders were spread over a microscopic slide and aninitial photomicrograph was taken. A few drops of water were slowlyadded at the edge of the cover slip using a micropipette.Photomicrographs at different intervals were taken to observe anyswelling of the particles upon exposure to water. FIGS. 9A and 9B depictthe swelling of a PLGA/PVA formulation and a PLGA/JPEG formulation,respectively. Both pictures show that water diffused into the particlesand particle diameter increased due to swelling.

Example 4 Adhesion Test Adhesion Test 1:

The formulation powder of PLGA/Chitosan/PVP was spread on the middle offilter paper to form a layer of dry powder. Slowly from one corner,water was applied to filter paper until the filter paper and powder bedbecame completely wet. The filter paper was allowed to dry completelyand observed for its film forming ability. The formulation formed a goodfilm after wetting and remained adhered to the filter paper.

Adhesion Test 2:

A formulation of particles made from PLGA/Alginate were sprayed over apiece of wet meat. The particle swelled and formed a good film over thesurface of the meat with excellent adhesion The film could not be washedoff by water.

Example 4 Manufacture of Exemplary Formulations

Manufacture of PLGA/Chitosan/PVP formulation (35:50:15)

-   1. Preparation of PLGA solution: An amount of acetone (350mL) was    transferred to a clean glass beaker. PLGA (3.5g) was slowly    transferred to acetone in beaker while stirring. Mixture in beaker    was vigorously stirred and mixed using magnetic stirrer until clear    1% solution was formed.-   2. Preparation of Chitosan solution: An amount of deionized (DI)    water (490 mL) was transferred to another clean glass beaker. Acetic    acid (10 mL) was added to water in a beaker and mixed well to make a    2% acetic acid solution in water. Chitosan (1g) was slowly added to    the solution and the solution was mixed. The mixing speed was    increased and continued until a clear solution was formed.-   3. Preparation of PVP solution: An amount of DI water (150mL) was    transferred to another clean beaker. An amount of PVP (0.3g) was    added to the water with mixing on another magnetic stirrer. The    mixing was continued until a clear 0.2% solution was formed.-   4. Preparation of formulation: Five parts of Chitosan solution    (500mL) and 1.5 parts of PVP solution (150mL) were mixed well in    another clean beaker and mixing was continued to form a uniform    solution.-   5. The Chitosan-PVP solution was then slowly added to 3.5 parts of    PLGA solution (350mL) with vigorously stirred with a magnetic    stirrer. Upon slow continuous addition, the solution started to form    a white milky solution or suspension.-   6. The stirring of the formed milky solution was continued with the    magnetic stirrer for about 16-18 hours in a hood to evaporate    acetone from formulation solution.-   7. Spray Drying: The formulation solution was then transferred to a    Yamato spray dryer to spray the formulation and form the formulation    microparticles.-   8. Before spraying the formulation solution, the spray dryer was    allowed to equilibrate by running it with DI water spray for at    least 15-20 min with set parameters.-   9. Once the spray dryer attained equilibrium with set parameters    (e.g., inlet temperature, drying air and atomizer temperature) the    formulation was fed to the spray dryer and continuously observed.    The formulation solution was continuously stirred on a magnetic    stirrer during spray drying process. All observable spray drying    parameters (e.g., outlet temperature, actual set temperature,    solution flow arte, gas pressure, spray nozzle size, etc.) were    monitored and recorded.-   10. Once the spray drying of the formulation spray was completed,    the spray dryer continued to run with DI water for at least 5 min    and slowly turned off to cool down by switching off the temperature,    drying air flow, and atomizer knobs.-   11. The formulation collection bottle was slowly unscrewed form the    unit and secured properly.

Example 5 Acute and Chronic Animal Studies

Acute and chronic studies of the performance of adhesion barriers werestudied. These studies were performed on adult dogs, pigs, and sheep. Inthese studies a surgical incision was made in the thorax of the studiedanimal and lung and heart were exposed. Formulations were deposited onthe exposed surface of the organ using a pressurized suspension of theparticles in HFA propellant.

In the acute studies, the particles were applied and the condition ofthe film formed from the particles was observed. In the chronic studies,the condition of the film was observed up to 23 days.

TABLE 3 Summary of Acute and Chronic animal studies. Formulation ChronicResults (% is wt %) Acute Results (after 23 days) 1 70/30 PLGA/PVAFormed good film — 80%/20% with consistent spray 2 Chitosan/PVA Formedexcellent film Formed excellent film 80%/20% immediately withimmediately with consistent spray consistentspray. No adhesion wasobserved, but some red cells. 3 Chitosan/PVP/PLGA Formed good film —30%/15%/55% with consistent spray 4 Chitosan/PVP/PLGA Formed excellentfilm Formed excellent film 50%/15%/35% immediately with immediately withconsistent spray consistent spray No adhesion was observed after 3 weeksimplant. Partial degradation with some material remaining.

FIG. 10 depicts a photograph of chronic sheep preparation at the time ofimplant. Formulation #2 and formulation #4 were sprayed over differentlung areas and heart areas for the formulation evaluation. A sectionwithout particles sprayed was used as control. The formulations can beenseen as they where initially applied to the sheep lung and heart.

FIG. 11 depicts a photograph of a chronic sheep implant at the time ofreexploration, 23 days after the initial implant. The photographdemonstrates the development of the biodegradable film/barrier on thesheep lung. No adhesion of tissue on either side of the film/barrier wasobserved.

FIG. 12 depicts a photograph of a chronic sheep implant at the time ofreexploration, 23 days after the initial implant. The photographdemonstrates the development of the biodegradable film/barrier over thesheep heart (left atrial appendage) and lung (the top portion of thephotograph), and the lack of adhesion formation on both sides of thebiodegradable film/barrier (between the heart and the barrier, andbetween the film/barrier and the lung).

FIG. 13 depicts a photograph from the same preparation as in FIG. 12showing another view of the biodegradable film/barrier over the heart(left atrial appendage), which clearly demonstrates lack of adhesionsand the development of a safe and easy to dissect film/barrier over theheart (left atrial appendage).

FIG. 14 depicts a photograph of a chronic sheep implant at the time ofreexploration, 23 days after the initial implant. The photograph clearlydemonstrates how the formulation has formed a film/barrier between thesheep lung (visceral pleura) and the chest wall (parietal pleura).

FIG. 15 depicts a photograph from the of chronic sheep implant in FIG.14, demonstrating the development of the biodegradable film/barrierwhich functioned as the adhesion barrier described in FIG. 14.

FIG. 16 depicts a photograph of histologic results of the biodegradablefilm/barrier depicted in FIG. 15. The histology shows a cleardelineation between the lung (visceral pleura), the barrier (TestArticle), and the perietal pleura (pleura). The biodegradablefilm/barrier (Test Article) creates a barrier by forming a typicalforeign body reaction (reactive fibrosis) resulting in a capsule orpseudo-membrane around the biodegradable film/barrier.

Example 6A-C Particle Size Control in Spray Drying Example 6A Effect ofAtomization Air Pressure on Particle Size

80% Chitosan/20%PVP Formulation

As the atomization air pressure changed from 0.15 to 0.1 MPa, theparticle size changed from 6 and 85 microns.

Example 6B Effect of Molar Composition of Polymers on Particle Size

TABLE 6 Particle size of PLGA/Chitosan/PVP formulation Particles sizeMolar (microns) 60/30/10 50 35/50/15 14

Example 6C Adding Surfactant Mannitol

A surfactant was added to a PLGA/Alginate formulation prior to spraydrying. Without surfactant, the particle size was 12 microns and withthe surfactant the particle size was 76 microns.

1-27. (canceled)
 28. A formulation for generating an adhesion barrierfilm comprising: a plurality of particles comprising: a combination ofpoly(L-lactide-co-glycolide) (PLGA) and alginate, a combination of PLGAand polyvinylpyrrolidone (PVP), a combination of PLGA and poly(vinyl)alcohol (PVA), a combination of PLGA and chitosan, or a combination ofchitosan and PVA; wherein: the formulation is in the form of a drypowder, the mean particle size is between about 700 nm and about 200microns; and when the formulation is deposited on a surface of internalbody tissue the deposited formulation absorbs moisture from the tissueand forms an adhesion barrier film configured to be adhered to thesurface, wherein the film is capable of reducing or preventing adhesionof the surface to other body tissue.
 29. The formulation of claim 28,wherein the particles swell and overlap when the particles absorbmoisture, wherein the swelling and overlap facilitates the formation ofthe film that reduces or prevents the adhesion.
 30. The formulation ofclaim 28, wherein the plurality of particles is uniformly suspended in aliquid, wherein the liquid has a boiling point below 0° C.
 31. Theformulation of claim 28, wherein when exposed to moisture, the particlesabsorb between 1 to 80 wt % water.
 32. The formulation of claim 28,wherein the film loses strength at a time between 30-60 days after theabsorption of the moisture.
 33. The formulation of claim 28, furthercomprising a therapeutic agent selected from the group consisting of ananti-inflammatory, anti-infective, hemostatic, chemotherapeutic, and anycombination thereof.
 34. The formulation of claim 33, wherein theanti-inflammatory agent is a corticosteroid.
 35. The formulation ofclaim 28, wherein the particles comprise PLGA, wherein the ratio ofL-lactide to glycolide in the PLGA is from 10/90 to 85/15.
 36. Theformulation of claim 28, wherein the PLGA is between about 10% to about90% and the alginate is between about 10% to about 90%, the PLGA isbetween about 10% to about 90% and the PVP is between about 10% to about90%, the PLGA is between about 10% to about 90% and the PVA is betweenabout 10% to about 90%, the PLGA is between about 10% to about 90% andthe chitosan is between about 10% to about 90%, or the chitosan isbetween about 10% to about 90% and the PVA is between about 10% to about90%.
 37. The formulation of claim 35, wherein the particles comprisePLGA and alginate.
 38. The formulation of claim 37, wherein theparticles comprise between about 10% to about 90% PLGA; and betweenabout 10% to about 90% alginate.
 39. The formulation of claim 35,wherein the particles comprise PLGA and chitosan.
 40. The formulation ofclaim 39, wherein the particles comprise between about 10% to about 90%PLGA; and between about 10% to about 90% chitosan.
 41. The formulationof claim 35, wherein the particles comprise PLGA and PVA.
 42. Theformulation of claim 41, wherein the particles comprise between about10% to about 90% PLGA; and between about 10% to about 90% PVA.
 43. Theformulation of claim 28, wherein the particles comprise one or moreadditional biodegradable polymers, water soluble polymers, or anycombination thereof.
 44. The formulation of claim 37, wherein theparticles further comprise PVP or chitosan.
 45. The formulation of claim28, wherein at least a portion of the plurality of particles ishygroscopic.
 46. The formulation of claim 28, the formulation furthercomprising an anti-inflammatory agent, wherein the biodegradable filmhas an anti-inflammatory effect such that inflammation is reduced orinhibited in a region of the surface of internal body tissue.
 47. Theformulation of claim 46, wherein the anti-inflammatory agent is acorticosteroid.
 48. The formulation of claim 28, wherein the pluralityof particles is in the form of a dry powder.